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Bio

Bio


My work focuses on our understanding of how cells and organisms maintain proteostasis in changing environments, which remains a poorly understood area of cell biology. Over the years, this has led me to study the cellular stress response in health and disease with an emphasis on the role of tandem repeats, intrinsically disordered domains and biomolecular phase separation. My goal is to translate fundamental biological insights into novel therapeutic approaches for human disease and tools for synthetic biology.

Professional Education


  • Doctor of Philosophy, Katholieke Universiteit Leuven (2017)
  • Bachelor of Science, Katholieke Universiteit Leuven (2010)
  • Master of Science, Katholieke Universiteit Leuven (2012)

Publications

All Publications


  • Designer condensates: a toolkit for the biomolecular architect. Journal of molecular biology Hastings, R. L., Boeynaems, S. n. 2021: 166837

    Abstract

    Protein phase separation has emerged as a novel paradigm to explain the biogenesis of membraneless organelles and other so-called biomolecular condensates. While the implication of this physical phenomenon within cell biology is providing us with novel ways for understanding how cells compartmentalize biochemical reactions and encode function in such liquid-like assemblies, the newfound appreciation of this process also provides immense opportunities for designing and sculpting biological matter. Here, we propose that understanding the cell's instruction manual of phase separation will enable bioengineers to begin creating novel functionalized biological materials and unprecedented tools for synthetic biology. We present FASE as the synthesis of the existing sticker-spacer framework, which explains the physical driving forces underlying phase separation, with quintessential principles of Scandinavian design. FASE serves both as a designer condensates catalogue and construction manual for the aspiring (membraneless) biomolecular architect. Our approach aims to inspire a new generation of bioengineers to rethink phase separation as an opportunity for creating reactive biomaterials with unconventional properties and to encode novel biological function in living systems. Although still in its infancy, several studies highlight how designer condensates have immediate and widespread potential applications in industry and medicine.

    View details for DOI 10.1016/j.jmb.2021.166837

    View details for PubMedID 33539874

  • ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization. Brain communications Tazelaar, G. H., Boeynaems, S. n., De Decker, M. n., van Vugt, J. J., Kool, L. n., Goedee, H. S., McLaughlin, R. L., Sproviero, W. n., Iacoangeli, A. n., Moisse, M. n., Jacquemyn, M. n., Daelemans, D. n., Dekker, A. M., van der Spek, R. A., Westeneng, H. J., Kenna, K. P., Assialioui, A. n., Da Silva, N. n., Povedano, M. n., Pardina, J. S., Hardiman, O. n., Salachas, F. n., Millecamps, S. n., Vourc'h, P. n., Corcia, P. n., Couratier, P. n., Morrison, K. E., Shaw, P. J., Shaw, C. E., Pasterkamp, R. J., Landers, J. E., Van Den Bosch, L. n., Robberecht, W. n., Al-Chalabi, A. n., van den Berg, L. H., Van Damme, P. n., Veldink, J. H., van Es, M. A. 2020; 2 (2): fcaa064

    Abstract

    Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated with the disease: intronic repeat expansions in C9orf72, polyglutamine expansions in ATXN2 and polyalanine expansions in NIPA1. Together with previously published data, the identification of an amyotrophic lateral sclerosis patient with a family history of spinocerebellar ataxia type 1, caused by polyglutamine expansions in ATXN1, suggested a similar disease association for the repeat expansion in ATXN1. We, therefore, performed a large-scale international study in 11 700 individuals, in which we showed a significant association between intermediate ATXN1 repeat expansions and amyotrophic lateral sclerosis (P?=?3.33 × 10-7). Subsequent functional experiments have shown that ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances amyotrophic lateral sclerosis phenotypes in Drosophila, further emphasizing the role of polyglutamine repeat expansions in the pathophysiology of amyotrophic lateral sclerosis.

    View details for DOI 10.1093/braincomms/fcaa064

    View details for PubMedID 32954321

    View details for PubMedCentralID PMC7425293

  • Symmetric dimethylation of poly-GR correlates with disease duration in C9orf72 FTLD and ALS and reduces poly-GR phase separation and toxicity. Acta neuropathologica Gittings, L. M., Boeynaems, S., Lightwood, D., Clargo, A., Topia, S., Nakayama, L., Troakes, C., Mann, D. M., Gitler, A. D., Lashley, T., Isaacs, A. M. 2019

    View details for DOI 10.1007/s00401-019-02104-x

    View details for PubMedID 31832771

  • Spontaneous driving forces give rise to protein-RNA condensates with coexisting phases and complex material properties PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Boeynaems, S., Holehouse, A. S., Weinhardt, V., Kovacs, D., Van Lindt, J., Larabell, C., Van Den Bosch, L., Das, R., Tompa, P. S., Pappu, R., Gitler, A. D. 2019; 116 (16): 7889?98
  • Spontaneous driving forces give rise to protein-RNA condensates with coexisting phases and complex material properties. Proceedings of the National Academy of Sciences of the United States of America Boeynaems, S., Holehouse, A. S., Weinhardt, V., Kovacs, D., Van Lindt, J., Larabell, C., Van Den Bosch, L., Das, R., Tompa, P. S., Pappu, R. V., Gitler, A. D. 2019; 116 (16): 7889?98

    Abstract

    Phase separation of multivalent protein and RNA molecules underlies the biogenesis of biomolecular condensates such as membraneless organelles. In vivo, these condensates encompass hundreds of distinct types of molecules that typically organize into multilayered structures supporting the differential partitioning of molecules into distinct regions with distinct material properties. The interplay between driven (active) versus spontaneous (passive) processes that are required for enabling the formation of condensates with coexisting layers of distinct material properties remains unclear. Here, we deploy systematic experiments and simulations based on coarse-grained models to show that the collective interactions among the simplest, biologically relevant proteins and archetypal RNA molecules are sufficient for driving the spontaneous emergence of multilayered condensates with distinct material properties. These studies yield a set of rules regarding homotypic and heterotypic interactions that are likely to be relevant for understanding the interplay between active and passive processes that control the formation of functional biomolecular condensates.

    View details for PubMedID 30926670

  • Axons Gonna Ride 'til They Can't No More. Neuron Boeynaems, S. n., Gitler, A. D. 2019; 104 (2): 179?81

    Abstract

    Prion-like domains have been implicated in protein phase separation and aggregation in cellular stress and neurodegeneration. In this issue of Neuron, Andrusiak et al. (2019) uncover a surprising role for a stress granule protein and phase separation in axon regeneration.

    View details for DOI 10.1016/j.neuron.2019.09.029

    View details for PubMedID 31647889

  • C9orf72-generated poly-GR and poly-PR do not directly interfere with nucleocytoplasmic transport. Scientific reports Vanneste, J. n., Vercruysse, T. n., Boeynaems, S. n., Sicart, A. n., Van Damme, P. n., Daelemans, D. n., Van Den Bosch, L. n. 2019; 9 (1): 15728

    Abstract

    Repeat expansions in the C9orf72 gene cause amyotrophic lateral sclerosis and frontotemporal dementia characterized by dipeptide-repeat protein (DPR) inclusions. The toxicity associated with two of these DPRs, poly-GR and poly-PR, has been associated with nucleocytoplasmic transport. To investigate the causal role of poly-GR or poly-PR on active nucleocytoplasmic transport, we measured nuclear import and export in poly-GR or poly-PR expressing Hela cells, neuronal-like SH-SY5Y cells and iPSC-derived motor neurons. Our data strongly indicate that poly-GR and poly-PR do not directly impede active nucleocytoplasmic transport.

    View details for DOI 10.1038/s41598-019-52035-6

    View details for PubMedID 31673013

  • Pour Some Sugar on TDP(-43). Molecular cell Boeynaems, S., Gitler, A. D. 2018; 71 (5): 649?51

    Abstract

    In this issue of Molecular Cell, McGurk etal. (2018) identify how poly(ADP-ribose) binding tunes the phase behavior of the ALS disease protein TDP-43, uncovering the molecular events underlying its aggregation in disease and illuminating a novel therapeutic target.

    View details for PubMedID 30193092

  • Pour Some Sugar on TDP(-43) MOLECULAR CELL Boeynaems, S., Gitler, A. D. 2018; 71 (5): 649?51
  • Molecular Dissection of FUS Points at Synergistic Effect of Low-Complexity Domains in Toxicity CELL REPORTS Bogaert, E., Boeynaems, S., Kato, M., Guo, L., Caulfield, T. R., Steyaert, J., Scheveneels, W., Wilmans, N., Haeck, W., Hersmus, N., Schymkowitz, J., Rousseau, F., Shorter, J., Callaerts, P., Robberecht, W., Van Damme, P., Van Den Bosch, L. 2018; 24 (3): 529-+

    Abstract

    RNA-binding protein aggregation is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). To gain better insight into the molecular interactions underlying this process, we investigated FUS, which is mutated and aggregated in both ALS and FTLD. We generated a Drosophila model of FUS toxicity and identified a previously unrecognized synergistic effect between the N-terminal prion-like domain and the C-terminal arginine-rich domain to mediate toxicity. Although the prion-like domain is generally considered to mediate aggregation of FUS, we find that arginine residues in the C-terminal low-complexity domain are also required for maturation of FUS in cellular stress granules. These data highlight an important role for arginine-rich domains in the pathology of RNA-binding proteins.

    View details for PubMedID 30021151

  • Protein Phase Separation: A New Phase in Cell Biology TRENDS IN CELL BIOLOGY Boeynaems, S., Alberti, S., Fawzi, N. L., Mittag, T., Polymenidou, M., Rousseau, F., Schymkowitz, J., Shorter, J., Wolozin, B., Van den Bosch, L., Tompa, P., Fuxreiter, M. 2018; 28 (6): 420?35

    Abstract

    Cellular compartments and organelles organize biological matter. Most well-known organelles are separated by a membrane boundary from their surrounding milieu. There are also many so-called membraneless organelles and recent studies suggest that these organelles, which are supramolecular assemblies of proteins and RNA molecules, form via protein phase separation. Recent discoveries have shed light on the molecular properties, formation, regulation, and function of membraneless organelles. A combination of techniques from cell biology, biophysics, physical chemistry, structural biology, and bioinformatics are starting to help establish the molecular principles of an emerging field, thus paving the way for exciting discoveries, including novel therapeutic approaches for the treatment of age-related disorders.

    View details for PubMedID 29602697

  • Phosphorylation Leads the Way for Protein Aggregate Disassembly DEVELOPMENTAL CELL Boeynaems, S., Gitler, A. D. 2018; 45 (3): 279?81

    Abstract

    Protein aggregation can be beneficial, with important biological functions, but must be somehow controlled. In this issue of Developmental Cell, Carpenter et al. (2018) uncover how a solid-like supermolecular protein assembly that regulates yeast meiosis is disassembled through phosphorylation of a disordered prion-like domain to control the timing of meiotic progression.

    View details for PubMedID 29738705

  • A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism ACTA NEUROPATHOLOGICA Swinnen, B., Bento-Abreu, A., Gendron, T. F., Boeynaems, S., Bogaert, E., Nuyts, R., Timmers, M., Scheveneels, W., Hersmus, N., Wang, J., Mizielinska, S., Isaacs, A. M., Petrucelli, L., Lemmens, R., Van Damme, P., Van den Bosch, L., Robberecht, W. 2018; 135 (3): 427?43

    Abstract

    The exact mechanism underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with the GGGGCC repeat expansion in C9orf72 is still unclear. Two gain-of-function mechanisms are possible: repeat RNA toxicity and dipeptide repeat protein (DPR) toxicity. We here dissected both possibilities using a zebrafish model for ALS. Expression of two DPRs, glycine-arginine and proline-arginine, induced a motor axonopathy. Similarly, expanded sense and antisense repeat RNA also induced a motor axonopathy and formed mainly cytoplasmic RNA foci. However, DPRs were not detected in these conditions. Moreover, stop codon-interrupted repeat RNA still induced a motor axonopathy and a synergistic role of low levels of DPRs was excluded. Altogether, these results show that repeat RNA toxicity is independent of DPR formation. This RNA toxicity, but not the DPR toxicity, was attenuated by the RNA-binding protein Pur-alpha and the autophagy-related protein p62. Our findings demonstrate that RNA toxicity, independent of DPR toxicity, can contribute to the pathogenesis of C9orf72-associated ALS/FTD.

    View details for DOI 10.1007/s00401-017-1796-5

    View details for Web of Science ID 000426057700007

    View details for PubMedID 29302778

  • ANTERIOR INTEROSSEOUS MONONEUROPATHY ASSOCIATED WITH HEV INFECTION NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION Swinnen, B., Boeynaems, S., Schrooten, M., Saegeman, V., Claeys, K. G., Van Damme, P. 2018; 5 (2): e429

    View details for DOI 10.1212/NXI.0000000000000429

    View details for Web of Science ID 000430190400002

    View details for PubMedID 29296634

    View details for PubMedCentralID PMC5745356

  • Phasing in on the cell cycle CELL DIVISION Boeynaems, S., Tompa, P., Van den Bosch, L. 2018; 13: 1

    Abstract

    Just like all matter, proteins can also switch between gas, liquid and solid phases. Protein phase transition has claimed the spotlight in recent years as a novel way of how cells compartmentalize and regulate biochemical reactions. Moreover, this discovery has provided a new framework for the study of membrane-less organelle biogenesis and protein aggregation in neurodegenerative disorders. We now argue that this framework could be useful in the study of cell cycle regulation and cancer. Based on our work on phase transitions of arginine-rich proteins in neurodegeneration, via combining mass spectroscopy with bioinformatics analyses, we found that also numerous proteins involved in the regulation of the cell cycle can undergo protein phase separation. Indeed, several proteins whose function affects the cell cycle or are associated with cancer, have been recently found to phase separate from the test tube to cells. Investigating the role of this process for cell cycle proteins and understanding its molecular underpinnings will provide pivotal insights into the biology of cell cycle progression and cancer.

    View details for PubMedID 29416553

  • Arginine-rich Peptides Can Actively Mediate Liquid-liquid Phase Separation BIO-PROTOCOL Boeynaems, S., De Decker, M., Tompa, P., Van Den Bosch, L. 2017; 7 (17)
  • Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics MOLECULAR CELL Boeynaems, S., Bogaert, E., Kovacs, D., Konijnenberg, A., Timmerman, E., Volkov, A., Guharoy, M., De Decker, M., Jaspers, T., Ryan, V. H., Janke, A. M., Baatsen, P., Vercruysse, T., Kolaitis, R., Daelemans, D., Taylor, J., Kedersha, N., Anderson, P., Impens, F., Sobott, F., Schymkowitz, J., Rousseau, F., Fawzi, N. L., Robberecht, W., Van Damme, P., Tompa, P., Van Den Bosch, L. 2017; 65 (6): 1044-+

    Abstract

    Liquid-liquid phase separation (LLPS) of RNA-binding proteins plays an important role in the formation of multiple membrane-less organelles involved in RNA metabolism, including stress granules. Defects in stress granule homeostasis constitute a cornerstone of ALS/FTLD pathogenesis. Polar residues (tyrosine and glutamine) have been previously demonstrated to be critical for phase separation of ALS-linked stress granule proteins. We now identify an active role for arginine-rich domains in these phase separations. Moreover, arginine-rich dipeptide repeats (DPRs) derived from C9orf72 hexanucleotide repeat expansions similarly undergo LLPS and induce phase separation of a large set of proteins involved in RNA and stress granule metabolism. Expression of arginine-rich DPRs in cells induced spontaneous stress granule assembly that required both eIF2? phosphorylation and G3BP. Together with recent reports showing that DPRs affect nucleocytoplasmic transport, our results point to an important role for arginine-rich DPRs in the pathogenesis of C9orf72 ALS/FTLD.

    View details for DOI 10.1016/j.molcel.2017.02.013

    View details for Web of Science ID 000396431900011

    View details for PubMedID 28306503

    View details for PubMedCentralID PMC5364369

  • Inside out: the role of nucleocytoplasmic transport in ALS and FTLD ACTA NEUROPATHOLOGICA Boeynaems, S., Bogaert, E., Van Damme, P., Van Den Bosch, L. 2016; 132 (2): 159?73

    Abstract

    Neurodegenerative diseases are characterized by the presence of protein inclusions with a different protein content depending on the type of disease. Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are no exceptions to this common theme. In most ALS and FTLD cases, the predominant pathological species are RNA-binding proteins. Interestingly, these proteins are both depleted from their normal nuclear localization and aggregated in the cytoplasm. This key pathological feature has suggested a potential dual mechanism with both nuclear loss of function and cytoplasmic gain of function being at play. Yet, why and how this pathological cascade is initiated in most patients, and especially sporadic cases, is currently unresolved. Recent breakthroughs in C9orf72 ALS/FTLD disease models point at a pivotal role for the nuclear transport system in toxicity. To address whether defects in nuclear transport are indeed implicated in the disease, we reviewed two decades of ALS/FTLD literature and combined this with bioinformatic analyses. We find that both RNA-binding proteins and nuclear transport factors are key players in ALS/FTLD pathology. Moreover, our analyses suggest that disturbances in nucleocytoplasmic transport play a crucial initiating role in the disease, by bridging both nuclear loss and cytoplasmic gain of functions. These findings highlight this process as a novel and promising therapeutic target for ALS and FTLD.

    View details for DOI 10.1007/s00401-016-1586-5

    View details for Web of Science ID 000380134400001

    View details for PubMedID 27271576

    View details for PubMedCentralID PMC4947127

  • Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD SCIENTIFIC REPORTS Boeynaems, S., Bogaertl, E., Michiels, E., Gijselinck, I., Sieben, A., Jovicic, A., De Baets, G., Scheveneels, W., Steyaert, J., Cuijt, I., Verstrepen, K. J., Callaerts, P., Rousseau, F., Schymkowitz, J., Cruts, M., Van Broeckhoven, C., Van Damme, P., Gitler, A. D., Robberecht, W., Van Den Bosch, L. 2016; 6

    Abstract

    Hexanucleotide repeat expansions in C9orf72 are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) (c9ALS/FTD). Unconventional translation of these repeats produces dipeptide repeat proteins (DPRs) that may cause neurodegeneration. We performed a modifier screen in Drosophila and discovered a critical role for importins and exportins, Ran-GTP cycle regulators, nuclear pore components, and arginine methylases in mediating DPR toxicity. These findings provide evidence for an important role for nucleocytoplasmic transport in the pathogenic mechanism of c9ALS/FTD.

    View details for DOI 10.1038/srep20877

    View details for Web of Science ID 000369936600001

    View details for PubMedCentralID PMC4751451

  • Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD. Scientific reports Boeynaems, S., Bogaert, E., Michiels, E., Gijselinck, I., Sieben, A., Jovicic, A., De Baets, G., Scheveneels, W., Steyaert, J., Cuijt, I., Verstrepen, K. J., Callaerts, P., Rousseau, F., Schymkowitz, J., Cruts, M., Van Broeckhoven, C., Van Damme, P., Gitler, A. D., Robberecht, W., Van Den Bosch, L. 2016; 6: 20877-?

    Abstract

    Hexanucleotide repeat expansions in C9orf72 are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) (c9ALS/FTD). Unconventional translation of these repeats produces dipeptide repeat proteins (DPRs) that may cause neurodegeneration. We performed a modifier screen in Drosophila and discovered a critical role for importins and exportins, Ran-GTP cycle regulators, nuclear pore components, and arginine methylases in mediating DPR toxicity. These findings provide evidence for an important role for nucleocytoplasmic transport in the pathogenic mechanism of c9ALS/FTD.

    View details for DOI 10.1038/srep20877

    View details for PubMedID 26869068

    View details for PubMedCentralID PMC4751451

  • Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS NATURE NEUROSCIENCE Jovicic, A., Mertens, J., Boeynaems, S., Bogaert, E., Chai, N., Yamada, S. B., Paul, J. W., Sun, S., Herdy, J. R., Bieri, G., Kramer, N. J., Gage, F. H., Van Den Bosch, L., Robberecht, W., Gitler, A. D. 2015; 18 (9): 1226-?

    Abstract

    C9orf72 mutations are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dipeptide repeat proteins (DPRs) produced by unconventional translation of the C9orf72 repeat expansions cause neurodegeneration in cell culture and in animal models. We performed two unbiased screens in Saccharomyces cerevisiae and identified potent modifiers of DPR toxicity, including karyopherins and effectors of Ran-mediated nucleocytoplasmic transport, providing insight into potential disease mechanisms and therapeutic targets.

    View details for DOI 10.1038/nn.4085

    View details for Web of Science ID 000360292600009

    View details for PubMedCentralID PMC4552077

  • Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nature neuroscience Jovicic, A., Mertens, J., Boeynaems, S., Bogaert, E., Chai, N., Yamada, S. B., Paul, J. W., Sun, S., Herdy, J. R., Bieri, G., Kramer, N. J., Gage, F. H., Van Den Bosch, L., Robberecht, W., Gitler, A. D. 2015; 18 (9): 1226-1229

    Abstract

    C9orf72 mutations are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dipeptide repeat proteins (DPRs) produced by unconventional translation of the C9orf72 repeat expansions cause neurodegeneration in cell culture and in animal models. We performed two unbiased screens in Saccharomyces cerevisiae and identified potent modifiers of DPR toxicity, including karyopherins and effectors of Ran-mediated nucleocytoplasmic transport, providing insight into potential disease mechanisms and therapeutic targets.

    View details for DOI 10.1038/nn.4085

    View details for PubMedID 26308983

  • Variable Glutamine-Rich Repeats Modulate Transcription Factor Activity MOLECULAR CELL Gemayel, R., Chavali, S., Pougach, K., Legendre, M., Zhu, B., Boeynaems, S., van der Zande, E., Gevaert, K., Rousseau, F., Schymkowitz, J., Babu, M., Verstrepen, K. J. 2015; 59 (4): 615?27

    Abstract

    Excessive expansions of glutamine (Q)-rich repeats in various human proteins are known to result in severe neurodegenerative disorders such as Huntington's disease and several ataxias. However, the physiological role of these repeats and the consequences of more moderate repeat variation remain unknown. Here, we demonstrate that Q-rich domains are highly enriched in eukaryotic transcription factors where they act as functional modulators. Incremental changes in the number of repeats in the yeast transcriptional regulator Ssn6 (Cyc8) result in systematic, repeat-length-dependent variation in expression of target genes that result in direct phenotypic changes. The function of Ssn6 increases with its repeat number until a certain threshold where further expansion leads to aggregation. Quantitative proteomic analysis reveals that the Ssn6 repeats affect its solubility and interactions with Tup1 and other regulators. Thus, Q-rich repeats are dynamic functional domains that modulate a regulator's innate function, with the inherent risk of pathogenic repeat expansions.

    View details for DOI 10.1016/j.molcel.2015.07.003

    View details for Web of Science ID 000362457900012

    View details for PubMedID 26257283

    View details for PubMedCentralID PMC4543046

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